Project Summary Psychotic symptoms of schizophrenia are associated with hyperactive dopaminergic signaling in striatal pathways. Currently available treatments for schizophrenia are often effective in ameliorating psychotic symptoms but induce adverse parkinsonian-like effects that limit their long-term utility. Given the shortcomings of current antipsychotics, it is imperative that novel approaches be identified that can decrease dopamine release to provide clinical efficacy with reduced adverse effect liability. The finding that the M1/M4-preferring muscarinic acetylcholine receptor (mAChR) agonist xanomeline demonstrates robust antipsychotic efficacy for all symptom clusters of schizophrenia, generated a major interest in developing selective M1 and M4 agents. Highly selective M4 positive allosteric modulators (PAMs) represent a promising therapeutic target for schizophrenia, but the mechanism underlying their antipsychotic efficacy is not well understood. Recent data from our laboratory suggests that selective activation of M4 receptors on medium spiny neurons results in a novel form of dopaminergic regulation and may, in part, be mediated by the metabotropic glutamate 1 receptor (mGlu1). We postulate that mGlu1 may provide a critical link for the antipsychotic-like effects of these compounds and may possess antipsychotic-like effects independently of M4 activation. However, validation of the therapeutic potential of mGlu1 has awaited development of an mGlu1 selective modulator. The Conn laboratory has successful developed both a positive and negative allosteric modulator (VU6004909 and VU0483650, respectively). This research proposal has been designed to develop the candidate?s technical research skills that are necessary to conduct independent neuropharmacology research, while having a positive impact on the field of glutamate systems biology and neuropsychiatric disorders. The proposed studies will bring together novel pharmacological and genetic tools to help define the functional roles of mGlu1 on neural circuity and subsequent antipsychotic-like actions. As such, we will utilize ex vivo and in vivo fast scan cyclic voltammetry (FSCV), optogenetics and behavioral assays to investigate whether mGlu1 co-activation is required for M4 PAMs antipsychotic effects and reduction in striatal dopamine release. In addition to providing important new insights into the antipsychotic-like effects of M4 PAMs, these studies, coupled with previous genetic studies in schizophrenia patients, raise the possibility that deficits in mGlu1 signaling could enhance midbrain DA signaling and symptoms associated with schizophrenia. Therefore, we will elucidate whether selective activation of mGlu1 will have antipsychotic-like effects and reduce DA release in a manner similar to that of M4 PAMs. The studies outlined in this application represent a major breakthrough that promises to allow fundamental advances in the therapeutic approach for the treatment of schizophrenia.